Head lice, Pediculus humanus capitis, are parasitic insects that mainly live and feed in the scalp and neck hairs of human hosts. A typical infested scalp of a patient with head lice houses about 20 female lice, which are prolific egg layers over the course of their 30-day life cycle. These eggs are cemented to the hair shaft and are commonly called nits. Head lice have a similar appearance to wingless ants. Like all insects, the parasite has a body that is constructed of a hard chitinous exoskeleton. The egg case that surrounds the nits is of similar construction and is glued to the hair shaft via a cement that is similar in characteristics to the hair keratin itself. Infections, irritation and lesions to the scalp are common side effects of head lice infestation. Head lice infestation is an oft occurring problem in the United States and is easily spread from direct head-to-head contact with an infected person's hair and common usage of combs and clothing. There are between 6 to 12 million annual head lice infestations in the United States. Grade school children suffer most from head lice infestations, with one result being an accumulation of absences from school, where lice outbreaks are believed to account for 12 million to 24 million missed days a year. A majority of public schools have instituted a no lice or a no lice and no-nit policy, forcing absenteeism on children and maybe forcing working parents to stay at home to look after them. For a review, see Burkhart and Burkhart (2006, Expert Opin. Drug Saf. 5(1):169-179).
Treatment for eliminating head lice traditionally included home remedies such as smearing mayonnaise, olive oil, a hair pomade, or some heavily viscous material about an infested scalp coupled with rigorous combing of the hair and meticulous removal of adult lice, nymphs, and nits. Though these home remedies do not kill head lice, the prevailing thought is that the viscosity of the material makes it hard for head lice to roam about the scalp, making for easy removal. Such home remedies are usually ineffective at controlling head lice due to the ability of the lice to revive rapidly once these materials are removed.
More effective treatments for eliminating head lice involve massaging the infested scalp with over-the-counter (OTC) topical creams containing active insecticides. Because of their potential toxicity to the human host, the use of these topical formulas are regulated by the FDA. Over-the-counter insecticides typically have pyrethrins or permethrin as active ingredients.
Pyrethrins are any one of six naturally occurring insecticides extracted from the chrysanthemum flower. Along with its synthetic derivative, permethrin, these molecules act on susceptible head lice by increasing sodium levels in the nervous system of the lice. The increased sodium levels cause membrane depolarization in the nervous system of the head lice, which eventually leads to spastic paralysis and death of the head lice.
When first introduced, both pyrethrin and permethrin were highly effective at eliminating susceptible lice. In the late 1980's, various formulations of both active ingredients had a high efficacy for eliminating adult head lice and their nits. However, recent reports indicate that treatment-resistant strains of head lice have evolved for Nix®, having 1% permethrin as an active ingredient, and various Rid® products, having approximately 0.33% pyrethrin as active ingredients. It comes as no surprise that strains of treatment-resistant head lice have been identified in both the United States and Europe due to the similar killing pathway for both insecticides.
Prescription products are also currently available and contain either lindane or malathion as the active ingredient. These insecticides specifically target the nervous system of the head lice. The chlorinated hydrocarbon, lindane, is formulated as a topical shampoo and is prescribed to treat head lice infestations. Lindane eliminates head lice by effectively slowing the insect's central nervous system causing paralysis and eventual death.
The reports of continued effectiveness of lindane for eliminating head lice is inconsistent at best. Reports on the efficacy of lindane for treating head lice have been listed from 17% in the U.S. to as high as 61% and 93% in other parts of the world. However, treating head lice with lindane poses problems for the human host. Side effects include toxicity to the central nervous system, convulsions, seizures; and it may be a carcinogen. Lindane has also been reported to have a slow killing time, and has poor ovicidal capacities.
Malathion is also available as a prescription insecticide to treat head lice infestations (e.g., OVIDE® an alcohol based lotion containing 0.5% malathion, terpeneol, dipentene and pine needle oil in 78% isopropyl alcohol). It is an organophospate that causes spastic paralysis and death in head lice.
As noted above, recently there has been an increase in strains of head lice which show resistance to available OTC and prescription treatments for head lice infestation. These parasites have adapted to chemical treatments using pyrethrins, permethrins, lindane, and malathion. In the US, permethrin resistant lice have been found in Massachusetts, Idaho, Texas, California and Florida. Single and dual resistance to pyrethrins/permethrins and malathion has been broadly reported in Great Britain (see Downs et al., 1999, Br. J. Dermatology 141:508-511).
Strains of head lice have been identified worldwide which are resistant to all currently available topical treatments. Possible neural damage to the human host prevents raising the insecticide levels above the current threshold in an attempt to combat these newer treatment-resistant head lice. One possible way to address this alarming increase in treatment resistant head lice would be to develop and introduce a topical pediculicide formulation which is (i) safe; (ii) effective against head lice infestation from both susceptible and treatment-resistant strains; (iii) is convenient for patient use; and, (iv) has not previously been marketed for such an indication. Such a strategy is disclosed herein by utilizing an anthelmintic agents derived from avermectin.
Avermectin is a natural fermentation product derived from the soil bacterium Streptomyces avermitilis. Avermectin naturally occurs as abamectin, a mixture of avermectin isomers containing >80% avermectin B1a and <20% avermectin B1b, see FIGS. 1A and 1B, respectively. Other semi-synthetic forms of avermectin and mutated forms of Streptomyces avermitilis containing avermectin, for example doramectin, ivermectin, selamectin, and eprinomectin have found medicinal uses as well.
Ivermectin is the synthetic dihydro form of avermectin and is an effective insecticide. These compounds have been shown to selectively bind with high affinity to glutamate-gated chloride ion channels (GluCl channels) as well as γ-aminobutyric acid (GABA) receptors, thus blocking the chemical transmission across the nerve synapses which utilize glutamate and GABA, respectively. This blockage, which occurs in invertebrate nerve and muscle cells, leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite.
The selectivity of ivermectin is attributable to the fact that some mammals do not have glutamate gated chloride channels and that the compound has a low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood brain barrier in humans. Thus, ivermectin has a documented history of highly safe and efficacious use in humans and animals. For example, over 400 million doses of orally formulated ivermectin have been used for controlling river blindness since 1986.
Ivermectin is commercially available as STROMECTOL® for eradication of Strongyloides stercoralis, which causes strongyloidiasis, and Onchocerca volvulus, which causes onchocerciasis. Ivermectin is also available as MECTIZAN® for eradication of Onchocerca volvulus and Wuchereria bancrofti. Ivermectin is usually available as a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihyro-25-(1-methylethyl) avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2 B1b, respectively, see FIG. 2A and FIG. 2B respectively.
Glaziou et al. (1994, Trop. Med. Parasitol. 45: 253-254) disclose treating humans with a single oral 200 ug/kg dose (n=26). Oral ivermectin was effective at this concentration against head lice. A second dose was suggested for prophylaxis, but not as part of the initial therapeutic regime.
Youssef et al. (1995, Amer. J. Trop. Med. Hyg. 53(6):652-653) describe a method of topical application of ivermectin to treat head lice.
Dunne et al. (1991, Trans. R. Soc. Trop. Med. Hyg. 85: 550-551) disclose results from a study wherein ivermectin was administered as a single oral dose of 100-200 ug/kg to treat head lice infestation. Positive, but not absolute, results where reported for this oral dosing regime.
U.S. Pat. No. 4,199,569, issued Apr. 23, 1980, discloses ivermectin, which as noted above is a semisynthetic, anthelmintic agent derived from the avermectins, a class of highly active broad-spectrum anti-parasitic agents isolated from the fermentation products of Streptomyces avermitilis. 
U.S. Pat. No. 6,103,248, issued to Burkhart and Burkhart, disclose a topical formulation for the treatment of head lice which includes a killing agent, and a lipophilic carrier having a viscosity within a range of from about 10,000 centipoise to about 85,000 centipoise at 21° C.
U.S. Pat. No. 6,524,602, also issued to Burkhart and Burkhart, disclose a topical formulation which includes a parasiticide and N,O-carboxymethyl-chitosan polymer, and a vehicle for the parasiticide and polymer.
U.S. Pat. No. 7,064,108, issued to Guzzo, et al., discloses an ivermectin-based topical gel composition comprising a pharmaceutically acceptable alcohol (30-40%; e.g., propylene glycol), a pharmaceutically acceptable glycol (30-40%; e.g., ethyl alcohol), and a pharmaceutically acceptable carrier. Ivermectin is contemplated at a w/v basis from 0.005 to 1.0%. Additional additives may include d-limonene, a nonionic surfactant and a pharmaceutically acceptable viscosifying agent (e.g., hydroxypropylcellulose).
U.S. Pat. No. 5,952,372, issued to William McDaniel, discloses methods of treating rosacea in humans involving orally-administered or topically-applied ivermectin. The topical aspect of the invention suggests a topical formulation with about 2% ivermectin.
U.S. Pat. Nos. 6,399,652; 6,399,651 and 6,319,945, issued to L. Dean Parks, disclose methods of treating skin disorders via application of topical formulations containing ivermectin to treat acne vulgaris (the '652 patent), a variety of dermatoses (e.g., transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions; the '651 patent) and seborrheic dermatitis (the '945 patent).
U.S. Pat. No. 6,262,031, issued to Larouche, et al. discloses an oral formulation of ivermectin to treat a head lice infestation.
It is evident that the OTC or prescription products presently available to the public for treatment or prevention of head lice each have their own significant drawbacks. Over-the-counter products such as pyrethrin and permethrin are presently compromised due to emerging strains of treatment-resistant head lice. On the other hand, the prescription products such as lindane and malathion carry recognized health risks and are also losing effectiveness due to the emergence of treatment-resistant lice. To this end, there remains a need for a patient friendly product that is safe and effective in treating susceptible and/or treatment-resistant head lice. The present invention addresses and meets this needs by disclosing an avermectin-based topical formulation and exemplifying an ivermectin-based topical formulation, and associated methods of use, which is safe, will appeal to the patient for ease of use and is shown to be effective against multiple strains of either susceptible and treatment-resistant head lice.